Meropenem-vaborbactam: a carbapenem and beta-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae

Abstract

Meropenem-vaborbactam is a carbapenem and β-lactamase inhibitor combination that is newly indicated for the treatment of complicated urinary tract infections (cUTI), including adult pyelonephritis. Vaborbactam was developed due to emergence of carbapenem-resistant strains of Enterobacteriaceae. In a phase I trial, patients that received meropenem-vaborbactam 2-2 g intravenously over 3 h every 8 h, C was 58.2 ± 10.8 μg/mL for meropenem and 59.0 ± 8.4 μg/mL for vaborbactam. AUC was 186 ± 33.6 μg • h/mL for meropenem and 204 ± 34.6 μg • h/mL for vaborbactam. V = 16.3 ± 2.6 L for meropenem and 17.6 ± 2.6 L for vaborbactam. Protein binding for vaborbactam averaged 33% in humans. Plasma clearance ranged from 10.42 ± 1.85 to 14.77 ± 2.84 L/h. One phase III trial evaluated efficacy for meropenem-vaborbactam 2-2 g intravenously every 8 h versus piperacillin-tazobactam 4-0.5 g intravenously every 8 h in complicated UTI. It found non-inferiority and statistical superiority for meropenem in overall success at the end of treatment primary end point. In another phase III trial evaluating efficacy in carbapenem-resistant Enterobacteriaceae (CRE) infections, meropenem-vaborbactam 2-2 g intravenously every 8 h was associated with decreased 28-day mortality and increased clinical cure compared with a best available therapy group.

β-lactam/β-lactamase inhibitor combinations: an update

“…4) is the first FDA-approved β-lactamase inhibitor containing a cyclic boronate pharmacophore. [18][19][20][21] The design of vaborbactam is the result of medicinal chemistry efforts to develop a cyclic boronate analog with selectivity towards bacterial β-lactamases over mammalian serine hydrolases. X-ray crystallography studies confirmed that vaborbactam forms a covalent adduct with the catalytic serine residue of CTX-M-15 and AmpC.…”

The carbapenem resistance gene blaOXA-23 is disseminated by a conjugative plasmid containing the novel transposon Tn6681 in Acinetobacter johnsonii M19

“…Carbapenems are considered to be reliable and effective antibiotic agents against most pathogenic bacteria because of their broad antibacterial spectrum [ 1 ] and are used in the treatment of serious nosocomial infections caused by cephalosporin-resistant bacteria [ 1 ]. Species of the Acinetobacter genus are extremely well adapted to the hospital environment and can easily become resistant to available antimicrobial agents; therefore, the isolation of carbapenem-resistant Acinetobacter species has raised increasing concerns [ 2 – 6 ].…”

The carbapenem resistance gene blaOXA-23 is disseminated by a conjugative plasmid containing the novel transposon Tn6681 in Acinetobacter johnsonii M19

“…Carbapenems are considered to be reliable and effective antibiotic agents against most pathogenic bacteria because of their broad antibacterial spectrum [1] and are used in the treatment of serious nosocomial infections caused by cephalosporin-resistant bacteria [1]. Species of the Acinetobacter genus are extremely well adapted to the hospital environment and can easily become resistant to available antimicrobial agents; therefore, the isolation of carbapenem-resistant Acinetobacter species has raised increasing concerns [2][3][4][5][6].…”